Dupilumab improves outcomes in patients with chronic rhinosinusitis with nasal polyps irrespective of gender: results from the SINUS‐52 trial

Abstract Objectives This post hoc analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS‐52 study; NCT02898454). Methods Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease‐specific health‐related quality of life (HRQoL) was assessed using the 22‐item Sino‐Nasal Outcome Test (SNOT‐22). Results The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT‐22 total score (56.6 vs. 49.1, P < 0.01) and more coexisting asthma (78.4% vs. 46.4%, P < 0.0001) and non‐steroidal anti‐inflammatory drug‐exacerbated respiratory disease (NSAID‐ERD) (38.7% vs. 18.8%, P = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were −2.33 (−2.80, −1.86) in male and −2.54 (−3.18, −1.90) in female patients (both P < 0.0001 vs. placebo), and for SNOT‐22 were −19.2 (−24.1, −14.2) in male and −24.4 (−31.5, −17.3) in female patients (both P < 0.0001 vs. placebo). There were no significant efficacy‐by‐gender interactions. Conclusion Female patients had greater asthma, NSAID‐ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.

Sex-and gender-related factors have been shown to affect the clinical presentation, outcomes and effects of therapies in a wide range of diseases 8,9 ; however, there is limited information on the impact of sex/gender in patients with CRSwNP.1][12][13][14] Differences in anatomic size, susceptibility to tobacco and hormonal factors have been speculated to increase the overall susceptibility to chronic rhinosinusitis in women compared with men. 11,13upilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13, which are central drivers of type 2 inflammation in CRSwNP and other inflammatory diseases. 1,15The efficacy and safety of dupilumab in CRSwNP was demonstrated in the SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) randomised, placebo-controlled trials. 16However, the efficacy of dupilumab by gender has not been studied in CRSwNP.
This post hoc analysis of the SINUS-52 study assessed the baseline characteristics and response to dupilumab treatment in male and female patients with severe CRSwNP.

DISCUSSION
Some differences in baseline disease characteristics were observed between male and female patients with severe CRSwNP who enrolled in the SINUS-52 study.Compared with male patients, female patients in the current analysis had a higher prevalence of coexisting asthma (78% vs. 46%) and coexisting NSAID-ERD (39% vs. 19%).These findings are consistent with a previous retrospective, single-centre study that reported higher frequencies of comorbid asthma (66% vs. 46%) and NSAID-ERD (13% vs. 5%) in female vs. male patients with CRSwNP. 13he baseline difference in HRQoL between male and female patients in the current analysis was statistically significant in the nasal and ear/facial domains of the SNOT-22 score, suggesting that these aspects of HRQoL may specifically affect female patients more than male patients.Similar data were reported previously in a study of patients with chronic rhinosinusitis undergoing endoscopic sinus surgery, which found that female patients reported more problems with postnasal drainage and facial pain than male patients. 12revious studies draw conflicting conclusions about the gender differences in CRSwNP.A retrospective review of patients with chronic rhinosinusitis (with and without nasal polyps) electing for endoscopic sinus surgery 12 and a surgical cohort study 14 reported a greater HRQoL impact in female vs. male patients with CRSwNP, 12,14 while a literature review 11 and a recent retrospective, single-centre cohort study 17 observed no significant gender differences.Differences in HRQoL measures, patient cohorts and study settings may explain these variable findings.For example, patients with CRSwNP and comorbid asthma and/or NSAID-ERD are known to have a greater disease burden and worse HRQoL than those without these comorbidities. 18There is also discordance in the literature regarding disease presentation in male and female patients with CRSwNP: one study showed no gender difference for NPS, 17 whereas others report more severe nasal congestion 10 and higher polyp scores 14 in male vs. female patients with CRSwNP.In our analysis, disease characteristics between male and female patients were generally the same, with the exception of lower HRQoL and the higher prevalence of coexisting asthma and NSAID-ERD in female patients.
Despite observed differences at baseline, dupilumab significantly improved SNOT-22 total and domain scores over 52 weeks irrespective of gender, with female patients achieving similar levels of mild/moderate disease severity as male patients by Week 52.The trend for greater improvement in SNOT-22 total and domain scores in female patients may reflect their higher baseline severity.
Loss of smell is one of the most troublesome and difficult-to-treat symptoms for patients with severe CRSwNP. 19In the general population, women are known to outperform men in olfactory ability, 20 but whether this difference translates into differences in olfactory outcomes in CRSwNP is not known.The current study found no significant differences between male and female patients with respect to smell improvement with dupilumab assessed using UPSIT or as self-reported by patients.
Overall, the results of this post hoc analysis show that, despite the higher HRQoL burden in female patients with CRSwNP, overall dupilumab efficacy was similar in male and female patients.The results add to the body of evidence demonstrating that dupilumab efficacy in CRSwNP is unaffected by a range of factors including patient phenotype, [21][22][23] disease endotype 3 and treatment history. 24,25isease characteristics were generally similar at baseline between male and female patients with CRSwNP, except that female patients had a greater asthma, NSAID-ERD and HRQoL burden than male patients.Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.

Study design and patients
Full details for the study design and patient eligibility of SINUS-52 have been published elsewhere. 16In brief, patients were randomised 1:1:1 to dupilumab 300 mg subcutaneous (SC) every 2 weeks (q2w) for 52 weeks, dupilumab 300 mg SC q2w to Week 24 and then every 4 weeks (q4w) to Week 52 or matching placebo for 52 weeks; all patients received daily background therapy with a stable dose of intranasal mometasone furoate nasal spray.The studies were conducted in accordance with Good Clinical Practice and with the principles ordained in the Declaration of Helsinki, the protocols were approved by appropriate ethical review boards and all patients provided written informed consent.

Statistical analyses
All analyses were conducted in patients treated with placebo or dupilumab 300 mg q2w from the intention-to-treat population.Baseline parameter P-values were computed using a Chi-square test for qualitative parameters.Baseline parameter P-values were computed using Wilcoxon rank-sum test for age, race, smoking and alcohol history quantitative parameters, and Kruskal-Wallis test for quantitative parameters.Differences in change from baseline between dupilumab and placebo, and interaction P-values for male vs. female patients, were determined using analysis of covariance (ANCOVA) models.The interaction P-value was computed by fitting an ANCOVA model with the corresponding baseline value, treatment group, asthma/non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) status, prior nasal polyp surgery and regions as covariates, plus the subgroup variable and the subgroup-by-treatment interaction.The placebo group and male subgroup were considered as references, respectively, for the treatment and NPS groups.All reported P-values are nominal.

DATA AVAILABILITY STATEMENT
Qualified researchers may request access to patient-level data and related study documents including clinical study reports, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications.Patient-level data will be anonymised, and study documents will be redacted to protect the privacy of trial participants.Further details on Sanofi's data sharing criteria, eligible studies and process for requesting access can be found at: https://www.vivli.org/.

Table 1 .
Baseline demographics and disease characteristics by gender LoS, loss of smell; NC, nasal congestion/obstruction; NP, nasal polyp; NPS, nasal polyp score; NSAID-ERD, non-steroidal anti-inflammatory drugexacerbated respiratory disease; SCS, systemic corticosteroid; SD, standard deviation; SNOT-22, 22-item Sino-Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test.All data are mean (SD) unless otherwise stated.Significant P-values are highlighted in bold.a Higher scores indicate greater disease severity, except for UPSIT, for which higher scores indicate lower disease severity.b n = 188.c Anosmia is defined as UPSIT < 19.ª 2024 The Authors.Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.

Table 2 .
LS mean difference (95% CI) for dupilumab vs. placebo in change from baseline at Week 52 in NPS, NC, LoS, UPSIT and SNOT-22 by gender Research was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. ClinicalTrials.govIdentifier: NCT02898454 (SINUS-52).The authors thank Asif H Khan (Sanofi) for his insights and guidance.Medical writing and editorial assistance were provided by Dr Peter Tran of Adelphi Group, Figure 2. LS mean differences for dupilumab vs. placebo in change from baseline at Week 52 in SNOT-22 total and domain scores by gender.***P < 0.0001 vs. placebo.LS, least squares; SNOT-22, 22-item Sino-Nasal Outcome Test.WJF receives research grants from BioInspire Technologies, GlaxoSmithKline, Meda Pharmaceuticals and Sanofi.CB is an advisory board member and receives speakers' fees from ALK, AstraZeneca, GlaxoSmithKline, Mylan, Novartis, Sanofi and Stallergenes Greer.AP, PJR and JAJ-N are employees and may hold stock and/or stock options in Sanofi.CH is an advisory board member of AstraZeneca, Dianosic, GlaxoSmithKline and Sanofi.OM reports no conflicts of interest.SN, YD and HS are employees and may hold stock and/or stock options in Regeneron Pharmaceuticals Inc. Formal analysis; investigation; writingoriginal draft; writingreview and editing.Claus Bachert: Formal analysis; investigation; writingoriginal draft; writingreview and editing.Claire Hopkins: Formal analysis; investigation; writingoriginal draft; writingreview and editing.Osama Marglani: Formal analysis; investigation; writingoriginal draft; writingreview and editing.Amy Praestgaard: Conceptualization; formal analysis; methodology; validation; writingoriginal draft; Conceptualization; formal analysis; methodology; writingoriginal draft; writingreview and editing.Yamo Deniz: Conceptualization; formal analysis; methodology; writingoriginal draft; writingreview and editing.Paul J Rowe: Conceptualization; formal analysis; methodology; writingoriginal draft; writingreview and editing.Harry Sacks: Conceptualization; formal analysis; methodology; writingoriginal draft; writingreview and editing.Juby A Jacob-Nara: Conceptualization; formal analysis; methodology; writingoriginal draft; writingreview and editing.